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G Struhl

Publications and source records attributed to G Struhl.

At least 37 records · Page 2Linked to original sources
PubMed1997

Different levels of Ras activity can specify distinct transcriptional and morphological consequences in early Drosophila embryos.

The terminal portions of the Drosophila body pattern are specified by the localized activity of the receptor tyrosine kinase Torso (Tor) at each pole of the early embryo. Tor activity elicits the transcription of two 'gap' genes, tailless (tll) and huckebein (hkb), in overlapping but distinct domains by stimulating the Ras signal transduction pathway. Here, we show that quantitative variations in the level of Ras activity can specify qualitatively distinct transcriptional and morphological responses. Low levels of Ras activity at the posterior pole direct tll but not hkb transcription; higher levels drive transcription of both genes. Correspondingly, low levels of Ras activity specify a limited subset of posterior terminal structures, whereas higher levels specify a larger subset. However, we also show that the response to Ras activity is not uniform along the body. Instead, levels of Ras activity which suffice to drive tll and hkb transcription at the posterior pole fail to drive their expression in more central portions of the body, apparently due to repression by other gap gene products. We conclude that tll and hkb transcription, as well as the terminal structures, are specified by two inputs: a gradient of Ras activity which emanates from the pole, and the opposing influence of more centrally deployed gap genes which repress the response to Ras.

Animals↗
PubMed1996

Direct and long-range action of a wingless morphogen gradient.

Wingless (Wg), a founding member of the Wingless/Int-1 (Wnt) family of secreted proteins, acts as a short-range inducer and as a long-range organizer during Drosophila development. Here, we determine the consequences of ectopically expressing (i) a wild-type form of Wg, (ii) a membrane-tethered form of Wg, and (iii) a constitutively active form of the cytosolic protein Armadillo (Arm), which normally acts to transduce Wg, and we compare them with the effects of removing endogenous Wg or Arm activity. Our results indicate that wild-type Wg acts at long range, up-regulating the transcription of particular target genes as a function of concentration and distance from secreting cells. In contrast, tethered Wg and Arm have only short-range or autonomous effects, respectively, on the transcription of these genes. We interpret these findings as evidence that Wg can act directly and at long range as a gradient morphogen during normal development.

Animals↗
PubMed1996

Dual roles for patched in sequestering and transducing Hedgehog.

Secreted proteins of the Hedgehog (Hh) family have diverse organizing roles in animal development. Recently, a serpentine protein Smoothened (Smo) has been proposed as a Hh receptor. Here, we present evidence that implicates another multiple-pass transmembrane protein, Patched (Ptc), in Hh reception and suggests a novel signal transduction mechanism in which Hh binds to Ptc, or a Ptc-Smo complex, and thereby induces Smo activity. Our results also show that Ptc limits the range of Hh action; we provide evidence that high levels of Ptc induced by Hh serve to sequester any free Hh and therefore create a barrier to its further movement.

Alleles↗
PubMed1996

Complementary and mutually exclusive activities of decapentaplegic and wingless organize axial patterning during Drosophila leg development.

Growth and patterning of the Drosophila leg are organized by three secreted proteins: Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Hh is secreted by posterior cells; it acts at short range to induce dorsal anterior cells to secrete Dpp and ventral anterior cells to secrete Wg. Here we show that the complementary patterns of dpp and wg expression are maintained by mutual repression: Dpp signaling blocks wg transcription, whereas Wg signaling attenuates dpp transcription. We also show that this mutual repression is essential for normal axial patterning because it ensures that the dorsalizing and ventralizing activities of Dpp and Wg are restricted to opposite sides of the leg primordium and meet only at the center of the primordium to distalize the appendage.

Animals↗
PubMed1996

Direct and long-range action of a DPP morphogen gradient.

During development of the Drosophila wing, the decapentaplegic (dpp) gene is expressed in a stripe of cells along the anteroposterior compartment boundary and gives rise to a secreted protein that exerts a long-range organizing influence on both compartments. Using clones of cells that express DPP, or in which DPP receptor activity has been constitutively activated or abolished, we show that DPP acts directly and at long range on responding cells, rather than by proxy through the short-range induction of other signaling molecules. Further, we show that two genes, optomotor-blind and spalt are transcriptionally activated at different distances from DPP-secreting cells and provide evidence that these genes respond to different threshold concentrations of DPP protein. We propose that DPP acts as a gradient morphogen during wing development.

Animals↗
PubMed1996

RNA recognition and translational regulation by a homeodomain protein.

In Drosophila, the primary determinant of anterior pattern is the gradient morphogen bicoid (bcd), a homeodomain protein that binds DNA and transcriptionally activates target genes at different threshold concentrations. Here we present evidence that bcd also binds RNA and acts as a translational repressor to generate an opposing gradient of the homeodomain protein caudal (cad). RNA binding by bcd seems to involve direct interactions between the bcd homeodomain and discrete target sequences within the 3' untranslated region of the cad messenger RNA and to block the initiation of cad translation.

Animals↗
PubMed1995

Similarities between trunk and spätzle, putative extracellular ligands specifying body pattern in Drosophila.

The basic body plan of Drosophila is specified by four determinant systems that organize pattern along the anteroposterior and dorsoventral axes. Two of these systems (anterior and posterior) depend on localized mRNAs. In contrast, the other two (ventral and terminal) require locally generated extracellular ligands that are transduced, respectively, by the transmembrane receptors Toll and torso (tor). The ligand for the Toll receptor is thought to be spätzle (spz), a secreted protein that is activated by proteolytic cleavage. Here we report that trunk (trk), a gene required for activity of the tor receptor, encodes a protein that resembles spz in several respects. In particular, the sequence suggests that trk is a secreted protein and that it contains an internal site for proteolytic cleavage. Furthermore, the carboxy-terminal domain of trk has a similar arrangement of cysteines to that of spz. We propose that trk encodes an extracellular ligand involved in specifying terminal body pattern and suggest by analogy with spz that a cleaved form of trk constitutes the ligand for the tor receptor.

Alleles↗
PubMed1995

Protein kinase A and hedgehog signaling in Drosophila limb development.

The Drosophila hedgehog (hh) gene encodes a secreted protein involved in organizing growth and patterning in many developmental processes. Hh appears to act by inducing the localized expression of at least two other signaling molecules, decapentaplegic (dpp) and wingless (wg), which then govern cell proliferation and patterning in surrounding tissue. Here, we demonstrate that cyclic AMP (cAMP)-dependent protein kinase A (PKA) is essential during limb development to prevent inappropriate dpp and wg expression. We also show that a constitutively active form of PKA can prevent inappropriate dpp and wg expression, but does not interfere with their normal induction by hh. We propose that the basal activity of PKA imposes a block on the transcription of dpp and wg and that hh exerts its organizing influence by alleviating this block.

Animals↗
PubMed1995

Sequential organizing activities of engrailed, hedgehog and decapentaplegic in the Drosophila wing.

The Drosophila wing is formed by two cell populations, the anterior and posterior compartments, which are distinguished by the activity of the selector gene engrailed (en) in posterior cells. Here, we show that en governs growth and patterning in both compartments by controlling the expression of the secreted proteins hedgehog (hh) and decapentaplegic (dpp) as well as the response of cells to these signaling molecules. First, we demonstrate that en activity programs wing cells to express hh whereas the absence of en activity programs them to respond to hh by expressing dpp. As a consequence, posterior cells secrete hh and induce a stripe of neighboring anterior cells across the compartment boundary to secrete dpp. Second, we demonstrate that dpp can exert a long-range organizing influence on surrounding wing tissue, specifying anterior or posterior pattern depending on the compartmental provenance, and hence the state of en activity, of the responding cells. Thus, dpp secreted by anterior cells along the compartment boundary has the capacity to organize the development of both compartments. Finally, we report evidence suggesting that dpp may exert its organizing influence by acting as a gradient morphogen in contrast to hh which appears to act principally as a short range inducer of dpp.

Animals↗
PubMed1994

Compartment boundaries and the control of Drosophila limb pattern by hedgehog protein.

Drosophila limbs are subdivided into anterior and posterior compartments which derive from adjacent cell populations founded early in development. Evidence is now provided that posterior cells organize growth and cell patterning in both compartments by secreting hedgehog protein and that hedgehog protein acts indirectly by inducing neighbouring anterior cells to secrete decapentaplegic or wingless protein.

Animals↗
PubMed1994

An oncogenic form of human raf can specify terminal body pattern in Drosophila.

Terminal portions of the Drosophila body pattern are specified by an extracellular ligand generated at each end of the early syncytial embryo. This ligand triggers the localized transcription of two gap segmentation genes, tailles (tll) and huckebein (hkb) through a signal transduction cascade involving the receptor tyrosine kinase torso (tor) and homologues of ras, raf, and mek (map kinae kinase). In contrast to the ligand, these signal transducing components are expressed ubiquitously. Here, we show that a constitutively active form of human raf1 protein can trigger tll and hkb transcription in Drosophila embryos and specify elements of the terminal body pattern. This result indicates a strong functional conservation between Drosophila and mammalian raf proteins and argues that the localized activity of Drosophila raf (D-raf) normally carries spatial information specifying the end portions of the body.

Animals↗
PubMed1993

Intrinsic activity of the Lin-12 and Notch intracellular domains in vivo.

The lin-12 gene of C. elegans and the Notch gene of D. melanogaster encode structurally related transmembrane proteins that mediate intercellular signaling. We show that truncated forms of these proteins consisting of only the intracellular domains cause cell fate transformations associated with constitutive activity in their respective organisms. This activity does not depend on endogenous gene function. Our results indicate that the intracellular domains of Lin-12 and Notch have intrinsic activity and that the principal role of the extracellular domains in the intact proteins is to regulate this activity. Our results also suggest that equivalent truncated forms of lin-12/Notch family members in vertebrates, including known oncogenes, are similarly active.

Anal Canal↗
PubMed1993

Down-regulation of the Drosophila morphogen bicoid by the torso receptor-mediated signal transduction cascade.

Anterior body pattern in Drosophila is specified by the graded distribution of the bicoid protein (bcd), which activates subordinate genes in distinct anterior domains. Subsequently, transcription of these target genes is repressed at the anterior pole owing to the activity of the receptor tyrosine kinase torso (tor). We show that both activation by bcd and repression by tor can be reproduced by a minimal promoter containing only bcd-binding sites upstream of a naive transcriptional start site. Repression requires the D-raf kinase and is associated with phosphorylation of bcd protein. Repression does not require either tailless or huckebein, which were previously thought to constitute the sole zygotic output of the tor signaling system. Finally, addition of a heterologous transcriptional activation domain to bcd renders the protein insensitive to tor-mediated repression. We propose that phosphorylation resulting from the activity of the tor signal transduction cascade down-regulates transcriptional activation by the bcd morphogen.

Animals↗
PubMed1993

The torso receptor localizes as well as transduces the spatial signal specifying terminal body pattern in Drosophila.

Specification of the end portions of the Drosophila body depends on the torso (tor) protein, a receptor tyrosine kinase that accumulates uniformly along the entire surface of the embryo but is activated only in the vicinity of the poles. Several genes are normally required for activating tor and appear to define a system in which a gene product tethered to the extracellular vitelline membrane at each end of the egg provides a local source for an extracellular tor ligand. This ligand would have to diffuse from the membrane to the cell surface of the embryo without losing its spatial localization. Here we report that the failure to accumulate tor protein at one or both poles leads to spatially inappropriate activity of more centrally located receptor. This ectopic activity depends on the same gene functions normally required for activating tor; thus we infer that it reflects inappropriate diffusion of the ligand to more central regions of the body. We conclude that the receptor not only transduces the spatial signal imparted by the tor ligand, but also ensures its correct localization by sequestering the ligand. Ligand trapping by receptor may also localize spatial signals in other patterning systems, including specification of the dorsal-ventral axis in Drosophila and of vulval cell fates in Caenorhabditis elegans.

Animals↗
PubMed1993

Organizing activity of wingless protein in Drosophila.

The adult appendages of Drosophila are formed from imaginal discs, sheets of epithelial cells that proliferate during larval development and differentiate during metamorphosis. wingless (wg, DWnt-1) protein, a putative signaling molecule, is expressed only in prospective ventral cells in each of the leg discs. To test the role of wg, we have generated randomly positioned clones of cells that express wg protein constitutively. Clones that arise in the prospective ventral portions of the leg discs develop normally. In contrast, dorsally situated clones give rise to ventrolateral patterns and exert a ventralizing influence on neighboring wild-type tissue. We propose that wg protein organizes leg pattern along the dorsoventral axis by conferring ventral positional information within the disc.

Animals↗
PubMed1992

Control of Drosophila body pattern by the hunchback morphogen gradient.

Most of the thoracic and abdominal segments of Drosophila are specified early in embryogenesis by the overlapping activities of the hunchback (hb), Krüppel, knirps, and giant gap genes. The orderly expression of these genes depends on two maternal determinants: bicoid, which activates hb transcription anteriorly, and nanos, which blocks translation of hb transcripts posteriorly. Here we provide evidence that the resulting gradient of hb protein dictates where the Krüppel, knirps, and giant genes are expressed by providing a series of concentration thresholds that regulate each gene independently. Thus, hb protein functions as a classical morphogen, triggering several distinct responses as a function of its graded distribution.

Animals↗
PubMed1991

RNA regulatory elements mediate control of Drosophila body pattern by the posterior morphogen nanos.

In Drosophila embryos, graded activity of the posterior determinant nanos (nos) generates abdominal segmentation by blocking protein expression from maternal transcripts of the hunchback (hb) gene. When active inappropriately at the anterior pole, nos can also block expression of the anterior determinant bicoid (bcd). We show that both regulatory interactions are mediated by similar sequences in the 3' untranslated region of each transcript. These nos response elements (NREs) are both necessary and sufficient to confer nos-dependent regulation, the degree of regulation determined by the number and quality of the elements and the level of nos in vivo. Based on these and other results, we argue that nos acts as a morphogen, controlling hb expression (and hence abdominal pattern) as a function of its concentration-dependent interaction with the NREs.

Animals↗